CN102477107B - Simple preparation method for mannosylated chitosan - Google Patents
Simple preparation method for mannosylated chitosan Download PDFInfo
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- CN102477107B CN102477107B CN 201010567176 CN201010567176A CN102477107B CN 102477107 B CN102477107 B CN 102477107B CN 201010567176 CN201010567176 CN 201010567176 CN 201010567176 A CN201010567176 A CN 201010567176A CN 102477107 B CN102477107 B CN 102477107B
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Abstract
The present invention relates to the field of polymer chemistry, and discloses a simple preparation method for mannosylated chitosan. According to the method, mannose and allyl alcohol are adopted as raw materials, formyl methyl mannopyranoside is prepared by carrying out a glycosylation reaction, an acetylation reaction of saccharide hydroxyl, an oxidation reaction of allyl, and a deacetylation reaction, and the formyl methyl mannopyranoside intermediate and the chitosan are subjected to a reductive amination reaction to prepare the mannosylated chitosan. According to the present invention, the reaction conditions of the synthetic route are mild, the operation is easy to perform, and the yield is high.
Description
Technical field
The present invention relates to chemical field.Be specifically related to a kind of simple and convenient process for preparing of mannose glycosylation chitosan.
Background technology
Chitosan is that a kind of chemical structure is the linear Portugal amine glycan of β-(1,4)-2-amino-2-deoxidation-D-Glucopyranose.Owing to have characteristics such as excellent biological compatibility, biodegradability and hypotoxicity, chitosan has been used for the mucosal delivery of genomic medicine as the genophore of safety.Chitosan is because of the Portugal's amido lotus positive electricity in the molecule; can be combined with the dna vaccination of bear electricity by electrostatic interaction and form particulate; this particulate can overcome vaccine through the physiology barrier of mucosal absorption; promote cellular uptake; and effectively protect in the dna vaccination idling fortune process and avoid nuclease degradation, thereby the immunogenicity of raising vaccine.The cell-specific of chitosan particle that carries dna vaccination is relatively poor, interesting is, the a large amount of mannose receptors of antigen presenting cell such as scavenger cell and dendritic cell surface expression, it is ligand modified that chitosan is carried out seminose, by receptor-mediated active targeting, can improve the chitosan particle of year dna vaccination effectively to the targeting of antigen presenting cell, promote cellular uptake, improve immunogenicity (the Tae Hee Kim of vaccine, et al.Journal of Nanoscience and Nanotechnology, 2006,6:2796-2803).Therefore, it is ligand modified that chitosan is carried out seminose, makes it become the carrier of more effective gene vaccine.
At present, the synthetic method of the relevant mannose glycosylation chitosan of bibliographical information has two kinds, and a kind of is directly to use isothiocyanic acid phenyl mannopyranose glycosides and chitosan are reacted, and makes the mannose glycosylation chitosan.KR20070029982 (A) discloses this kind preparation method.But expensive to isothiocyanic acid phenyl mannopyranose glycosides, practicality is lower, and through the synthetic mannose glycosylation chitosan of this route, the bridge formation between seminose and chitosan is N-phenylthiourea base.MayuHashimoto etc. disclose the preparation method of another kind of mannose glycosylation chitosan, namely utilize formyl methyl mannoside and chitosan to carry out reductive amination process and make mannose glycosylation chitosan (Mayu Hashimoto et al.Biotechnol Lett, 2006,8 (11): 815-821).The synthetic method of formyl methyl mannoside is as follows: by Ke Nixisi-Ke Nuoer glycosylation reaction, utilize mercury cyanide catalysis halo glucosides to make the allyl group mannoside; Then-78 ℃ of following ozone oxidation allyl group mannosides make the formyl methyl mannoside (Kevin R.Holme, et al.Carbohydrate Research, 1992,225:291-306).Ozone oxidation reaction condition harshness in this synthetic route needs very low temperature device and specific preparation ozone devices.Need high pressure in the ozone preparation process, in addition, the high local concentrations ozone that reaction produces can cause atmospheric pollution, harmful to human.Even more noteworthy, the high-concentrated ozone that reaction produces can with oxygen mix, bring bigger potential safety hazard.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, the gentle easily control of a kind of reaction conditions, the mannose glycosylation Preparation of Chitosan novel method that operational condition easily realizes, cost is lower, yield is higher are provided.
Technical scheme of the present invention is to prepare the mannose glycosylation chitosan by formyl Methyl mannoside and chitosan reaction.The mannose glycosylation chitosan that this route is synthetic is bridge formation with the ethyl between seminose and chitosan, does not introduce any group that may cause physiological action, so that the chitosan of seminose after modifying do not strengthen its cytotoxicity.In the reaction of preparation formyl Methyl mannoside, we are at first with acid catalyst catalysis glycosylation reactions such as p-methyl benzene sulfonic chloride or camphorsulfonic acids, directly introduce allyl group in seminose 1-OH previous step, avoid the preceding halo glucosides step of Ke Nixisi-Ke Nuoer glycosylation reaction, simplified reaction scheme.For fear of using ozone, at first to 2,3 of seminose; 4,6-position sugar hydroxyl carries out the acetylize protection, subsequently under the activation of catalyzer perosmic anhydride; adopt sodium periodate to 1-allyl group-2,3,4; allyl group in 6-O-ethanoyl-mannopyranose glycosides carries out oxidation; make formyl methyl-2,3,4; 6-O-ethanoyl-mannopyranose glycosides carries out namely getting the formyl Methyl mannoside after deacetylated to it.Protect in the reaction of sugared hydroxyl in acetylize, protect the reaction times of sugared hydroxyl by controlling acetylize, can realize the selectivity preparation to mannose derivative α, beta comfiguration.Whole piece synthetic route equipment requirements is low, and the reaction conditions gentleness is controlled, and the product yield is higher, has avoided use ozone, has reduced the danger of reaction.
The synthetic method reaction formula of mannose glycosylation chitosan of the present invention is as follows:
The concrete preparation method of mannose glycosylation chitosan of the present invention may further comprise the steps:
(1) adding of D-seminose is contained in the vinyl carbinol of acid catalyst, 90 ℃ of back flow reaction 8～24h generate 1-allyl group-D-mannopyranose glycosides.Add diacetyl oxide in the pyridine solution of 1-allyl group-D-mannopyranose glycosides, reaction 3～12h gets 1-allyl group-2,3,4,6-O-ethanoyl-mannopyranose glycosides;
(2) with 1-allyl group-2,3,4,6-O-ethanoyl-mannopyranose glycosides adds the dioxane/water solution of perosmic anhydride, behind stirring reaction 1～2h, in reaction solution, add the sodium periodate saturated aqueous solution, stirring at room 24～48h gets 1-formyl methyl-2,3,4,6-O-ethanoyl-mannopyranose glycosides;
(3) to 1-formyl methyl-2,3,4, in the absolute methanol solution of 6-O-ethanoyl-mannopyranose glycosides, add sodium methylate/absolute methanol solution, 45 ℃ of back flow reaction 5～60min get the formyl Methyl mannoside;
(4) the formyl Methyl mannoside is added in the chitosan solution, add sodium cyanoborohydride again, stirring at room 24～48h namely gets target product mannose glycosylation chitosan.
Among the preparation method of the present invention, the catalyzer that seminose and vinyl carbinol carry out glycosylation reaction is Lewis acid or solid strong acid, as p-methyl benzene sulfonic chloride, camphorsulfonic acid etc.Preferred p-methyl benzene sulfonic chloride.
Among the preparation method of the present invention, acetylization reaction 3～5h, α, beta comfiguration proportion of products are 1: 1; Acetylization reaction 5～12h, α, beta comfiguration proportion of products are 9: 1.
Among the preparation method of the present invention, the dioxane/water solution of catalyzer perosmic anhydride activation 1-allyl group-2,3,4 behind 6-O-ethanoyl-mannopyranose glycosides 1～2h, adds the sodium periodate saturated solution again, makes that the sodium periodate oxidation effect is easy to carry out.
Among the preparation method of the present invention, 1-allyl group-2,3,4,6-O-ethanoyl-mannopyranose glycosides and sodium periodate mol ratio are 1: 2～3.
Among the preparation method of the present invention, chitosan solution is acetic acid/sodium acetate buffer solution of pH 5.5.
Among the preparation method of the present invention, reduction amination reagent sodium cyanoborohydride and chitosan mol ratio are 4: 1.
Preparation method of the present invention, formyl Methyl mannoside and chitosan molar feed ratio not simultaneously, the mannose glycosylation chitosan substitution value difference of gained.Mol ratio is 1: 2～14 o'clock, and the mannose group substitution value is 7%～60%; Mol ratio is 1: 5～14 o'clock, and the mannose group substitution value is 7%～20%.Preferred substitution value is 7%～20%.
Preparation method of the present invention, selected mannose glycosylation chitosan purification process can be dialysis method.Suitably the dialysis tubing room temperature of molecular weight cut-off dialysis reaction solution is 4～7 days, the elimination insolubles, and the filtrate freeze-drying, namely.
Preparation method of the present invention, selected mannose glycosylation chitosan purification process can be the isopropanol precipitating method.The Virahol that adds 10～20 times of volumes in the reaction solution is separated out mannose glycosylation chitosan precipitation, and dehydrated alcohol is washed 2 times, the 12000rpm frozen centrifugation, and vacuum-drying or vacuum lyophilization precipitation, namely.
The preferred dialysis method of the purification process of mannose glycosylation chitosan.
Mannose glycosylation chitosan of the present invention is buff powder, is dissolved in acidic aqueous solution, and along with the increase of substitution value, solubleness increases in the water.Synthesis technique of the present invention is simple, and the reaction conditions gentleness is controlled, and each goes on foot reaction yield and all reaches more than 70%, and overall yield reaches 47%-57%, can realize producing and amplify, and has broad application prospects.
Embodiment
Deacetylating degree of chitosan is more than 95%, viscosity-average molecular weight 115kDa; Reagent is analytical pure and chemical pure; The molecular weight cut-off of dialysis tubing is 14000 (MWCO 14000).
Embodiment 1
The mol ratio of formyl Methyl mannoside and chitosan is 1: 14 enforcement
1.1-the preparation of α-allyl group-D-mannopyranose glycosides
The adding of 1.5gD-seminose is contained in the 10mL vinyl carbinol of 8.2mg p-methyl benzene sulfonic chloride, 90 ℃ of backflows, stirred overnight, vinyl carbinol is removed in decompression, gets 2g brown syrup shape 1-allyl group-D-mannopyranose glycosides.
1-allyl group-D-mannopyranose the glycosides of step reaction gained in 50 ℃ of dissolvings of 15ml pyridine, after placing cooling, add the 13.5mL diacetyl oxide, stirring is spent the night, and after reacting completely reaction solution is poured in the 50mL frozen water, the glass stick vigorous stirring, the 15mL ethyl acetate extraction, separatory, 3 * 15mL ethyl acetate extraction water, merge organic phase, 3 * 20mL 5%NaHCO
3Wash organic phase, anhydrous MgSO
4Dry organic phase 1h filters, and filtrate decompression boils off solvent, silica gel column chromatography separating purification (ethyl acetate: sherwood oil=1: 3), get 2.7g colourless syrup shape 1-α-allyl group-2,3,4,6-O-ethanoyl-mannopyranose glycosides, yield 83%.
1H?NMR(300MHz，CDCl
3)：δ5.88(dddd，1H，CH
2＝CH-)，5.23-5.40(m，5H，H-2，3，4，CH
2＝CH-)，4.87(d，1H，H-1)，4.29(dd，1H，J
6a，6b＝12.3Hz，J
5，6a＝3.6Hz，H-6a)，4.19(dd，1H，J＝12.6Hz，J＝5.1Hz，CH
2＝CH-CH
2O)，4.11(dd，1H，J＝12.3Hz，J
5，6b＝2.4Hz，H-6b)，4.02-4.06(m，2H，H-5，CH
2＝CH-CH
2O)，1.99，2.04，2.11，2.16(4s，12H，CH
3CO)
2.1-α-formyl methyl-2,3,4, the preparation of 6-O-ethanoyl-mannopyranose glycosides
With 1.2g 1-α-allyl group-2,3,4,6-O-ethanoyl-mannopyranose glycosides is dissolved in the 22mL dioxane/water mixed liquid that contains the 15mg perosmic anhydride (20: 2).After stirring 1h, in reaction solution, add sodium periodate saturated aqueous solution (containing the 1.5g sodium periodate), stirring at room 48h.10mL CH
2Cl
2Termination reaction leaves standstill separatory, 3 * 10mL CH
2Cl
2The wash water phase merges organic phase.2 * 10mL saturated common salt washing organic phase, anhydrous MgSO
4Dry 1h.Filter, filtrate decompression boils off solvent, silica gel column chromatography separating purification (ethyl acetate: sherwood oil=1: 2), get 0.881g colourless syrup shape 1-α-formyl methyl-2,3,4,6-O-ethanoyl-mannopyranose glycosides, yield 74%.
1H?NMR(300MHz，CDCl
3)：δ9.74(t，1H，-CHO)，5.27-5.42(m，3H)，4.90(d，1H)，4.24-4.31(m，3H)，4.09-4.18(m，2H)，2.01，2.05，2.10，2.17(4s，12H，CH
3CO)
3.1-the preparation of α-formyl methyl-mannopyranose glycosides
With 0.881g 1-α-formyl methyl-2; 3; 4; 6-O-ethanoyl-mannopyranose glycosides is dissolved in the 13.5mL anhydrous methanol, adds 1.1mL 0.2M sodium methylate/absolute methanol solution, stirs 1h in 45 ℃; concentrating under reduced pressure; silica gel column chromatography separating purification (methyl alcohol: ethyl acetate=1: 5), get 0.5g micro-yellow powder shape 1-α-formyl methyl-mannopyranose glycosides, yield 99%.
1H?NMR(300MHz，D
2O)：δ5.09(t，J＝4.8Hz，1H)，4.81(s，1H)，3.80(m，1H)，3.64-3.74(m，2H)，3.59(m，1H)，3.53(m，1H)，3.42-3.49(m，2H)，3.31(dd，J＝10.2Hz，5.1Hz，1H)
4. the preparation of mannose glycosylation chitosan
16mg 1-α-formyl methyl-mannopyranose glycosides is added in chitosan acetic acid/sodium acetate buffer solution of 10.4mL 16.1mg/mL, after the dissolving, add the 0.271g sodium cyanoborohydride, stirring at room 48h fully.After reacting completely, distilled water room temperature dialysis reaction solution 7 days, the elimination insolubles, the filtrate freeze-drying gets light yellow end product mannose glycosylation chitosan 173mg, yield 94%.
FT?IR：2924，2879，1655，1152，1072，1031，898cm
-1
1H?NMR(300MHz，D
2O/CF
3COOD)：δ4.44(H1)，3.31-3.87(H
3，H
4，H
5，H
6，H
2′，H
3′，H
4′，H
5′，H
6′，Ha)，2.91(H
2)，2.63(H
b)，1.96(-NH-COCH
3)
It is 7.7% that substitution value is calculated in ultimate analysis.
Embodiment 2
The molar feed ratio of formyl Methyl mannoside and chitosan is 1: 7 enforcement
Except the molar feed ratio of 1-α-formyl methyl-mannopyranose glycosides and chitosan is 1: 7, the preparation condition of 1-α-formyl methyl-mannopyranose glycosides is with embodiment 1.The detailed preparation process of mannose glycosylation chitosan is as follows:
32mg 1-α-formyl methyl-mannopyranose glycosides is added in chitosan acetic acid/sodium acetate buffer solution of 10.4mL 16.1mg/mL, after the dissolving, add the 0.543g sodium cyanoborohydride, stirring at room 48h fully.After reacting completely, in distilled water, be 14000 dialysis tubing room temperature dialysis reaction solution 7 days with molecular weight cut-off, the elimination insolubles, the filtrate freeze-drying gets light yellow end product mannose glycosylation chitosan 177mg, yield 89%.
FT?IR：2924，2873，1655，1149，1073，1028，898cm
-1
1H?NMR(300MHz，D
2O/CF
3COOD)：δ4.44(H
1)，3.31-3.87(H
3，H
4，H
5，H
6，H
2′，H
3′，H
4′，H
5′，H
6′，Ha)，2.91(H
2)，2.63(H
b)，1.96(-NH-COCH
3)
It is 11.2% that substitution value is calculated in ultimate analysis.
Embodiment 3
The mol ratio of formyl Methyl mannoside and chitosan is 1: 5 enforcement
Except the mol ratio of 1-α-formyl methyl-mannopyranose glycosides and chitosan is 1: 5, the preparation condition of 1-α-formyl methyl-mannopyranose glycosides is with embodiment 1.The detailed preparation process of mannose glycosylation chitosan is as follows:
92mg 1-α-formyl methyl-mannopyranose glycosides is added in chitosan acetic acid/sodium acetate soln of 20.8mL 16.1mg/mL, after the dissolving, add 1.550g sodium cyanoborohydride, stirring at room 48h under the vigorous stirring fully.After reacting completely, distilled water room temperature dialysis reaction solution 7 days, the elimination insolubles, the filtrate freeze-drying gets light yellow end product mannose glycosylation chitosan 359mg, yield 84%.
FT?IR：2924，2873，1654，1149，1072，1028，898cm
-1
1H?NMR(300MHz，D
2O/CF
3COOD)：δ4.44(H1)，3.31-3.87(H
3，H
4，H
5，H
6，H
2′，H
3′，H
4′，H
5′，H
6′，H
a)，2.91(H
2)，2.63(H
b)，1.96(-NH-COCH
3)
It is 19.9% that substitution value is calculated in ultimate analysis.
Claims (4)
1. the preparation method of a mannose glycosylation chitosan, it is characterized in that: be raw material with seminose and vinyl carbinol, under the acid catalyst effect, reflux is carried out glycosylation reaction, carry out acetylization reaction under glucosides product and the diacetyl oxide room temperature, make 1-allyl group-2,3,4,6-O-ethanoyl-mannopyranose glycosides, 1-allyl group-2,3,4, carry out oxidizing reaction under 6-O-ethanoyl-mannopyranose glycosides and the strong oxidizer room temperature, and then take off acetyl protection and make the formyl Methyl mannoside, formyl Methyl mannoside and chitosan carry out reductive amination process under the room temperature in acetic acid/sodium-acetate buffer of pH5.5, make the mannose glycosylation chitosan, wherein said acid catalyst is selected from Lewis acid or solid strong acid; Described strong oxidizer is the Periodic acid solution that contains the catalyzer perosmic anhydride; Formyl Methyl mannoside and chitosan mol ratio are 1: 5～14 o'clock, and the mannose group substitution value is 7%～20%; Acetylization reaction 3～5h, α, beta comfiguration proportion of products are 1: 1; Reaction 5～12h, α, beta comfiguration proportion of products are 9: 1.
2. the described preparation method of claim 1, it is characterized in that: Lewis acid is p-methyl benzene sulfonic chloride, solid strong acid is camphorsulfonic acid.
3. the described preparation method of claim 1 is characterized in that: the dioxane/water solution activation 1-allyl group-2,3,4 of perosmic anhydride behind 6-O-ethanoyl-mannopyranose glycosides 1～2h, adds sodium periodate saturated solution reaction 24～48h.
4. the described preparation method of claim 3, it is characterized in that: 1-allyl group-2,3,4,6-O-ethanoyl-mannopyranose glycosides and sodium periodate mol ratio are 1: 2～3.
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| CN105754017B (en) * | 2016-03-11 | 2018-07-20 | 浙江医药高等专科学校 | Mannose is grafted the preparation method and applications of trimethyl chitin |
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